MICROCIRCULATORY INJURY DURING MYOCARDIAL PRESERVATION

At the present time a major obstacle to clinical heart
transplantation programs is a shortage of donor organs. This
obstacle arises primarily from our inability to preserve the
function of the isolated organ for longer than 3-4 hours after
harvest from the donor. The result of inadequate preservation is
a damaged organ that does not function adequately once transplanted
into a recipient. The long-range goal of the proposed studies is
to overcome this obstacle by development of improved long-term
myocardial preservation techniques. To accomplish this goal the
mechanisms of injury underlying failure of current procedures must
be identified and strategies for circumventing them discovered.
Our preliminary results suggest the following hypothesis: that the
decreased contractile function observed in hearts preserved for 24
hours is directly related to injury sustained by the
microcirculation during the preservation period. The result of the
injury to the microcirculation is loss of functional vessels and
ischemia. The general strategy of the proposed studies is to
examine the relationship between parameters of flow during and
after the preservation period as they relate to contractile
function, with an emphasis on identifying the mechanism of injury
to the microcirculation. Rabbit hearts will be used in the
studies. Initially, they will be preserved by continuous perfusion
with a cardioplegia solution at low pressure and temperature.
Reperfusion will occur in vitro and in vivo, the latter making use
of a heterotopic transplant model. Contractile function, coronary
flow, microvascular function (percentage of flowing capillaries,
permeability and density), and ultrastructural alterations will be
measured. Specific questions and goals include: Are coronary flow rate and
microcirculatory function, in terms of the percentage of vessels
supporting flow, related? Preliminary evidence indicates that the
answer to this question is yes. Is contractile function upon
reperfusion related to microcirculatory function during the
preservation period? Are the alterations of microcirculatory
function reversible with reperfusion? Are vessels permanently lost
as a result of the long-term preservation procedure? The site of
block within the vascular tree will be localized and the injury,
in terms of ultrastructural abnormalities, will be characterized.
The mechanisms of injury which might underlie the alteration of
microcirculatory function will be examined. Possible mechanisms
include: 1) a mechanical problem of inadequate pressure, and 2)
vascular damage due to lack of blood constituents in the perfusate. These studies will provide new information for the development of
long-term preservation techniques. If the studies are successful,
the information could lead to alleviation of the donor shortage
problem.